In one form or another, chronic and poorly healing wounds constitute a major burden on the UK health system. Moreover, in certain member countries of the EU health expenses relating to wound healing are already approaching the third most expensive drain on health care funding.
A Chronic wound is herein defined as one exhibiting delayed or defective healing which does not progress through the predictable stages of the healing process (as described below). Commonly, chronic wounds are classified into three broad categories: venous ulcers, diabetic, and pressure ulcers. Long-term venous insufficiency accounts for 70% to 90% of chronic wounds and commonly affects the elderly. Venous insufficiency results in venous hypertension, in which blood flow is abrogated resulting in subsequent ischaemia. Venous insufficiency can occur as a result of obstructions to venous outflow or reflux due to valve damage. Following a period of ischaemia, tissue reperfusion can result in reperfusion injury, causing the tissue damage that leads to wound formation.
Chronic foot ulcers are a major complication of diabetes, accounting for up to 25% of all hospital admissions involving diabetes, and at a cost to the UK National Health Service of £250M annually. Chronic foot ulcers cause substantial morbidity, impair the quality of life, and are the major cause of lower limb amputation. Despite careful attention to foot care, as many as 25% of diabetics develop foot ulcers in their lifetimes. The causes of lower limb ulceration are the same in diabetics as in non-diabetics, namely neuropathy, ischaemia and trauma. However, this “pathogenic triad” predisposes wounds to infection, which can also contribute to the non-healing nature of the wounds.
Pressure wounds are another major resource health cost. They are typically caused by failure to provide routine nursing or medical care. In the UK 412,000 people are affected annually by this sort of wound at a cost of £1.4-2.1 billion.
Furthermore, chronic wounds can also be categorised by whether they are caused by surgery, burns, dermatitis, vasculitis or radiation.
Current wound treatment strategies involve removing pressure from the area, debridement, wound dressing and management of infection: surgical resection and vascular reconstruction may be required in more advanced disease, which ultimately may necessitate amputation. These strategies commonly seek to address problems that are associated with chronic wounds, such as bacterial load, ischaemia, and imbalance of proteases, all of which can further affect the wound healing process.
The healing of a wound is controlled by complex biological processes that involve a diverse number of cell types; complex interactions between cells and tissues; the activation of the immune system and the activation of the angiogenic process. Moreover, all of these processes involve a large number of molecules.
A typical healing process can be divided into 5 distinct, but closely related, stages: clotting stage, acute inflammation stage, matrix deposition stage, capillary formation stage and re-epithelialisation stage. A diverse number of factors are involved in and control each of these stages. Deficiencies in any aspect of the process may result in defective wound healing. Thus, a ‘normal’ healing process may be defective as a result of either intrinsic or external factors, which manifest as ‘abnormal non-healing’ or ‘chronic’ wounds. It is these chronic or ‘non-healing’ wounds that present the greatest challenge to the quality of a patient's life and mounting expenses to the healthcare system.
A chronic wound often arises from failure to progress through the normal stages of wound healing, whereby an initial injury resulting in a wound cannot subsequently be repaired. Changes occur within the molecular environment of a chronic wound, such as high levels of inflammatory cytokines or proteases, and low levels of growth factors, these changes detain or terminate the healing process and increase the potential for septic infections. By enhancing or manipulating factors that contribute to wound healing it may therefore be possible to correct the process, thereby reducing the likely occurrence of a chronic wound, or accelerate its subsequent repair.
PTPRK
Protein tyrosine phosphatise receptor type K, PTPRK, is also known as DKFZp686C2268, DKFZp779N1045 and R-PTP-kappa. It is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signalling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPRK possesses an extracellular region, a single transmembrane region, and two tandem catalytic domains, and thus represents a receptor-type PTP. The extracellular region contains a meprin-A5 antigen-PTP mu (MAM) domain, an Ig-like domain and four fibronectin type III-like repeats. Moreover, PTPRK has been shown to mediate homophilic intercellular interaction, possibly through the interaction with beta- and gamma-catenin at adherens junctions. Expression of the PTPRK gene has been found to be stimulated by TGF-beta 1, which may be important for the inhibition of keratinocyte proliferation. In cancer, PTPRK has been found to be suppressed in aggressive tumours as shown by our recent study in breast cancer (Sun et al, SABCS, Cancer Res 2010).
While the biochemical functions of the PTP family is known to some degree, the therapeutic implication of the PTPRK enzyme has rarely been explored, particularly in relation to wound healing.
We, therefore, have surprisingly discovered that PTPRK has a role to play in wound healing. Indeed, we have discovered that the expression of this protein impedes the wound healing process. Moreover, the inhibition of PTPRK promotes wound healing.
Inhibitors of PTPRK are known. The most readily available is a salt of stibogluconate. Sodium stibogluconate is a medicine used to treat leishmaniasis, a disease resulting from infection by one of over 20 different species of the Leishmania species of parasite. Sodium Stibogluconate belongs to the class of medicines known as the pentavalent antimonials. Whilst its exact paracidal effect on the Leishmania parasite is unknown it is thought that the parasite is killed by inhibition of glucose catabolism resulting in reduced ATP synthesis, thereby decreasing subsequent macromoleular synthesis and preventing replication.
Sodium stibogluconate is sold in the United Kingdom as PENTOSTAM™ (manufactured by GlaxoSmithKline) and is currently only available for administration by injection. Unfortunately, widespread resistance to this medicine has limited the utility of sodium stibogluconate, and in many parts of the world, amphotericin or miltefosine is used instead to treat leishmaniasis.
In summary, we have identified at least one molecular target for treating wounds and in particular human wounds. More particularly, but not exclusively, said molecular target has application in the treatment of chronic wounds. The molecular target is PTPRK and therefore the invention relates to a novel therapeutic comprising an inhibitor of either, or both, PTPRK expression or PTPRK activity. In the former instance, the invention involves a novel gene therapy approach and in the latter instance a novel protein therapy approach. Accordingly, the invention also relates to a novel therapeutic comprising an inhibitor of either, or both, PTPRK expression or PTPRK activity. In the former instance, the invention involves a novel gene therapy approach and in the latter instance a novel protein therapy approach.
Reference herein to PTPRK, is reference to a gene or protein whose identity is shown in FIG. 16.
Our invention can improve the quality of a patient's life by ensuring that new wounds do not deteriorate into a chronic state and existing chronic wounds can be treated in a way that actively promotes healing.